Project Summary Photoreceptors in the retina are highly polarized and compartmentalized neurons. Delivering and confining proteins to a specific compartment is essential for most, if not all, cellular activities that occur in photoreceptors. The photoreceptor outer segment (OS) is a primary cilium-related compartment specialized for phototransduction, and intraflagellar transport (IFT) is a mechanism that moves proteins along the ciliary axoneme in both anterograde (from the basal body to the OS distal end) and retrograde (from the OS distal end to the basal body) directions. While roles and mechanisms of protein trafficking to the OS including anterograde IFT are under active investigation and relatively well understood, the presence and mechanisms of protein trafficking in the opposite (retrograde) direction are left largely unexplored. In the proposed studies, we will investigate the presence and roles of retrograde IFT in photoreceptors. In Aim 1, we will determine the presence of active retrograde protein trafficking by IFT in the photoreceptor OS. Aim 2 will be devoted to defining the specific roles of retrograde IFT in photoreceptors compared to that of anterograde IFT. The outcome of these studies is expected to fundamentally advance our understanding of the molecular mechanisms of polarized protein distribution in photoreceptors and provide a novel insight into the pathomechanisms of inherited retinal degenerations associated with defective retrograde protein trafficking.